Splenic Mechanisms in the Pathogenesis of Anaemia A
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POSTGRAD. MED. J. (1965), 41, 748 Postgrad Med J: first published as 10.1136/pgmj.41.482.748 on 1 December 1965. Downloaded from SPLENIC MECHANISMS IN THE PATHOGENESIS OF ANAEMIA A. J. BOWDLER, M.D., B.Sc., M.R.C.P. T. A. J. PRANKERD, M.D., F.R.C.P. from the M.R.C. Research Group in Haemolytic Diseases, University College Hospital Medical School, London, W.C.1. ANAEMIA is not infrequently accompanied by the presence of marrow infiltration. Further, enlargement of the spleen, and in some in- red cell output has 'to be assessed in relation stances, as in the haemorrhagic anaemia of to red cell lifespan, which may also alter after portal hypertension, it is clear that both spleno- splenectomy, and the marrow response to a megaly and anaemia arise from a common shortened red cell lifespan is only imperfectly factor. The reasons for the relationship of known. A frequently quoted figure for red splenomegaly and anaemia are less easily dis- cell production in states of chronic haemolysis cerned in other conditions, such as pernicious is six to eight times the normal rate (Crosby anaemia and iron deficiency states. In a third and Akeroyd, 1952). However, Mollison (1956) group there is evidence for the dependance found output as high as 12 times normal in a of the anaemia on the presence of the enlarged patient with paroxysmal nocturnal haemoglo- spleen, and it is in these that the investigation binuria, and we have investigated a man of of the spleen is most significant in view of the 18 years with antiglobulin-positive autoimmuneProtected by copyright. possibility of correcting the anaemia by splen- haemolytic disease who maintained a haemato- ectomy. crit of 20.5% despite a mean red cell lifespan The role of the spleen in producing anaemia of 3.5 days, indicating a red cell output of has been frequently discussed in terms of two 16 times normal. Following splenectomy, the principal mechanisms, the first being the dep- spleen was 'found to weigh more than 700 g. It ression of red cell production, and the second is thus clear that splenomegaly per se is in- the direct destruction of red cells during their sufficient 'to impair erythropoiesis, although passage through the organ. Recent work has this does not-necessarily exclude the possibility tended to focus less attention on the possible of a depressant effect by the spleen in other dyshaemopoietic influence of the spleen and conditions. has emphasized the complexity of the relation- ship between the organ and the circulating red Splenic Destruction in situ cell. The pulp of the spleen consists of venous sinuses between which run the pulp cords of and Billroth. The over the and Splenomegaly Erythropoiesis controversy direction http://pmj.bmj.com/ The possibility of marrow depression arising degree of the blood flow through the cords is from a presumptive humoral influence of the still unresolved, but in man the circulation is spleen (has been frequently considered, for probably of -the mixed variety, both open and instance by Moeshlin (1956), Cohen, Gardner closed channels being present (Weiss, 1959) and Barnett (1961a and b) and Dameshek although the direct sinusoidal pathway is (1960). Motulsky, Casserd, Giblett, Broun and thought to predominate (Prankerd, 1963). Finch (1958), in dismissing such a mechanism, Barnett and Lewis (1961) have pointed out stated that they had never obtained satisfactory that 'the red cells may sometimes pass through on October 6, 2021 by guest. evidence for it, but Wetherley-Mein, Jones and what is functionally a mesenchymal mass, Pullan (1961) have presented radio-iron studies honeycombed with channels lined by reticular of patients with myeloid metaplasia before and cells, which brings the blood cells into close after splenectomy which were consistent with contact with the macrophage system. The an improvement in marrow function following structure is therefore well adapted to be a site removal of 'the spleen. of active erythrophagocytosis. The problem is an especially difficult one to In normal circumstances in man, the spleen evaluate: marrow depression in the presence of plays only a small part in the destruction of splenomegaly, as in lymphomata, acute and red cells, sharing this function with other chronic leukaemias, and the lipidoses, may be components of the macrophage system due to other effects of the disease, especially in (Prankerd, 1963). In many abnormal circum- December, 1965 BOWDLER and PRANKERD: Splenic Mechanisms 749 Postgrad Med J: first published as 10.1136/pgmj.41.482.748 on 1 December 1965. Downloaded from stances, however, the spleen may become the pool, or a balanced interchange between the principal site for the destruction of red cells, pool and the general circulation, in which as shown both by the accumulation of iron in case ;the rate of entry could be much greater. the tissues, and by qthe progressive deposition This arises from the fact that in a steady state, of chromium-51 in the spleen after the intra- any irreversible loss of cells from the general venous injection of labelled red cells (Jandl, circulation must be balanced by an equivalent Greenberg, Yonemoto and Castle, 1956; release of new cells from the bone marrow, Hughes Jones and Szur, 1957; McCurdy and which imposes a constraint on the maximum Rath, 1958). Such a situation may result from rate of loss under such conditions. abnormalities of the endogenous red cells, as Conditions of rapid interchange between the in hereditary spherocytosis or elliptocytosis, or general circulation and the splenic pool can an abnormality mainly in the spleen itself such be demonstrated either by following the second- that normal transfused cells may also be ary rise in splenic radioactivity after the destroyed even in the absence of demonstrable intravenous injection of isotope-labelled cells antibodies, a situation sometimes encountered by means of a scintillation counter (Motulsky, in thalassaemia major. Casserd and Giblett, 1956; Harris, McAlister The concept has arisen of "splenopathic and Prankerd, 1958) or by estimating the anaemia", for instance in leukaemia, in which associated fall in the blood radioactivity the enlarged spleen, by reason of its increased (Motulsky and others, 1958). Simultaneous size, exerts a deleterious and destructive effect measurements of blood and spleen aotivity on the red cell '(Dameshek and Gunz, 1959). It have been found to produce patterns consistent is certainly true that massive splenomegaly is with the concept of two-pool interchange. frequently accompanied by a reduction in the Evidence for irreversible is pooling more diffi- Protected by copyright. red cell lifespan, but this is not necessarily so, cult to obtain, but such a possibility may at least within the limits ,that can be assessed sometimes be inferred (Bowdler, 1962), and in by the chromium-51 method (Bowdler, 1965). some conditions it is olear that both inter- Further, even when shortened survival is pre- changing and irreversible pools are present sent, this is not necessarily corrected by splenec- together. tomy, and a spleen of large size cannot in all Splenic pooling of red cells has been shown instances be held to imply excessive destruction in hereditary spherocytosis, autoimmune hae- within the organ. molytic disease, chronic myeloid leukaemia, thalassaemia major, myeloid metaplasia, perni- Red Cell Pooling cious anaemia, Hodglin's disease and in sickle- In certain haemolytic states the spleen has a cell disease when splenomegaly is present, high red cell content, sometimes representing a although not every case of these diseases will substantial fraction of the total red cell mass. show the phenomenon. Pooling may also occur Such intrasplenic red cells might be considered in the normal spleen when abnormal cells are in the until introduced into the Harris and irreversibly trapped organ destroyed circulation; http://pmj.bmj.com/ in situ. Alternatively, they might be regarded as others (1958) demonstrated this with naturally a population exchanging with the red cells of occurring and artificial spherocytes and with the general circulation. Thirdly, since these antibody-coated cells, while Bowdler (1962) are not mutually exclusive possibilities, some found it to occur with,the cells of a spleneoto- cells might be irreversibly trapped while others mized thalassaemic donor. In many instances could still return to the extrasplenic circulation. in which pooling occurs there are abnormalities For some authors the term "sequestration" in the shape or volume of the red cells, which implies cell trapping by the spleen with sub- may affect the rate of transit of such cells at on October 6, 2021 by guest. sequent destruction of the cells in the organ, the level of the communications between the but in general it is preferable to keep the splenic cords and the sinuses. However, gross difference between pooling and destruction quite changes in the cells are not necessarily present, distinct as the two processes are not necessarily and more subtle alterations of the cell surface, associated. such as the depletion of lipid (Harris, McAlister The spleen may contain a substantial frac- and Prankerd, 1957) or blockade of sulphydryl tion of the total red cells of the body despite groups (Jacobs and Jandl, 1962) are also the absence of progressive anaemia and this effective. must imply either prolonged survival of the It is clear then that in many conditions, the cells before destruction by the organ, with a red cells may spend intermittent periods packed relatively slow rate of entry of cells to the within the pulp of the spleen, a situation which 750 POSTGRADUATE MEDICAL JOURNAL December, 1965 Postgrad Med J: first published as 10.1136/pgmj.41.482.748 on 1 December 1965. Downloaded from in many respects can be regarded as metabo- production of anti-erythrocyte antibodies in lically disadvantageous, as shown by the low autoimmune haemolytic disease.